1. Field of the Invention
The present invention relates to a method for inhibiting the release of interleukin 1 (IL-1) from IL-1 producing cells. More specifically, the invention relates to the treatment of diseases associated with elevated levels of IL-1.
2. Background Information
IL-1, a polypeptide cytokine with multiple biological properties, is a key mediator in immunological reactions as well as in the body's response to microbial invasion, inflammation and tissue injury. Since IL-1 is also highly inflammatory, down-regulation of its production has been an area of intense investigation. Specific pathological conditions where Il-1 diminution is beneficial include inflammatory diseases such as arthritis (where IL-1 is found in high concentrations in synovial fluid), endotoxemia (where, in conjunction with tumor necrosis factor the high concentration of IL-1 contributes to fever, hypothermia and hemodynamic shock), granulomatous diseases, fibrosis and hypersensitivity diseases (C. D. Dinarello, Review of Infect. Dis. 6, 51 (1986)).
At present, the most effective therapeutic agents to treat diseases associated with elevated IL-1 levels are corticosteroids. These act by inhibiting IL-1 transcription, although they may stimulate IL-1 translation of preformed IL-1 messenger RNA (mRNA). (P. J. Knudsen et al, J. Immunol. 139, 4129 (1987)). More recently, IL-1 receptor antagonists have been described that block the activity of IL-1 by binding to IL-1 receptors (C. H. Hannum et al., Nature 343, 336 (1990)).
It has now been found that aromatic diamidines are effective in treating diseases associated with elevated IL-1 levels. For example, 1,5-bis(4-amidinophenoxy)pentane (pentamidine), an aromatic diamidine known for its effectiveness against AIDS related Pneumocystis carinii pneumonia, is a specific and effective inhibitor of cellular IL-1 release from macrophages. This may be associated with its putative ability to inhibit protease activity, since release of IL-1 from the membrane bound form is dependent upon the action of proteases which hydrolyze the peptide bond between the membrane anchoring sequence and the secreted form (K. Matsushima et al., J. Immunol. 136, 2883 (1986)).
The use of pentamidine as a blocker of IL-1 is an improvement over the use of corticosteroids. Pentamidine allows the protein to be translated, but blocks IL-1 at the level of release while corticosteroids block IL-1 at the level of mRNA. By contrast, corticosteroids block the message of IL-1 from being formed. This mechanism of action by corticosteroids is nonspecific, in that this class of drugs blocks the transcription of many biologically important proteins, as well as blocking IL-1 formation.
In addition, the mechanism by which pentamidine appears to act (the alteration of a postranslational protein modification event) allows it to be much more selective when compared to a representative corticosteroid, for example, dexamethasone. Such selectivity by pentamidine serves to spare other components of the immune system and circumvent the overt broad immunotoxicity that often results in decreased host resistance in patients undergoing corticosteroid therapy. This mechanism is a vast improvement over the immunodepressive activity of the corticosteroids.
1,5-di(4-imidazolinophenoxy)pentane, an aromatic substituted diamidine known for its effectiveness against Trypanosoma rhodesiense and Plasmodium berghei (E. Steck et al., Exp. Parasitol. 42, 404 (1981)), has also been found to be a specific and effective inhibitor of cellular IL-1 release from macrophages. This imidazoline is an analog to pentamidine and has a similar structure, with the exception that the terminal amidino groups are substituted with imidazoline moieties. Thus, this compound is believed to exert its effects in a way that is mechanistically similar to pentamidine.